There is increasing evidence that serotonin (5HT) neurotransmission plays an important modulatory role in the development of drug addiction. One promising target for the actions of 5HT are the 5HT6 receptors (5HT6Rs), given their high density in limbic brain regions, such as the nucleus accumbens (NAc). The overall aim of the proposed experiments, therefore, is to use molecular approaches to elucidate the role of 5HT6Rs in modulating the rewarding effects of cocaine. It is hypothesized that overexpression of 5HT6Rs in the NAc will attenuate cocaine-induced conditioned place preference (CPP), as well as both cocaine- and stress-induced reinstatement of the CPP. In contrast, it is predicted that both downregulation and blockade of 5HT6Rs in the NAc will potentiate cocaine-induced CPP. Finally, it is hypothesized that one way in which 5HT6Rs may modulate the rewarding effects of cocaine is by regulating the phosphorylation states of the phosphoprotein DARRP-32. These experiments will provide additional insight into the role of 5HT6Rs in drug experience-dependent behavioral plasticity and will contribute to the further understanding of the processes that mediate the behavioral and neurobiological changes thought to underlie addiction.